Artemisinin mediates neuroprotection against Parkinson’s disease by targeting Adcy5-Gch1-BH4 axis
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus Norvegicus
SUBMITTER: 
Feng Zhang
PROVIDER: PXD043573 | iProX | Thu Jul 06 00:00:00 BST 2023
REPOSITORIES: iProX
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Project description:Dopaminergic (DA) neurons are the predominant cell type in the midbrain that synthesize dopamine, a neurotransmitter implicated in various behavioural processes, including motor function, the reward pathway, and satiety. In diseases affecting these neurons, such as in Parkinson’s disease (PD), there is growing evidence that the gut-brain axis and selective vulnerability of DA neurons plays a crucial role in disease. Most investigations relating to DA neurons in the gut rely on immunoreactivity to tyrosine hydroxylase (TH) - a rate-limiting enzyme in the production of dopamine. However, the reliability of TH staining as a marker of DA neurons has been questioned in recent years. Our aim is to perform a comprehensive characterization of DA neurons in the gut using a well-accepted reporter mouse line, expressing a fluorescent protein under the dopamine transporter promoter (DAT). Our findings confirm a unique localization of DA neurons in the gut, and unveil that there are discrete subtypes of DA neurons in the gut, which we characterized using both immunofluorescence and single-cell transcriptomics. We observed distinct subtypes of DAT neurons expressing co-transmitters and modulators across both plexuses; some of them likely co-releasing acetylcholine, and a smaller population likely releasing nitric oxide; while others were positive for a slew of canonical DA markers (Vmat2, Girk2, Foxa2). Given the clear heterogeneity of DA gut neurons, further investigation is warranted to define their functional signatures and discover their inherent biological differences that predispose these cells to neurodegeneration.
2023-07-16 | GSE237170 | GEO
Project description:Tyrosine hydroxylase (TH) is a highly regulated enzyme that catalyses the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines. Mutations and dysfunction in this enzyme lead to DA deficiency and parkinsonisms of different severity. An understanding of TH deficiency at the level of structure and stability has been lacking to date, as only structures of truncated TH forms have been available. Here, we used cryoEM and XL-MS to determine the high-resolution structure of full-length human tetrameric TH in the absence and presence of the end-product and feedback inhibitor DA bound to the active site
2021-12-22 | PXD024519 | Pride
Project description:Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson’s disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Tyrosine hydroxylase (TH), the first and rate-limiting enzyme for dopamine synthesis, is a well-established marker for mDA neurons. Here, we report the generation of a human embryonic stem cell (hESC) line with a TH-RFP (red fluorescent protein) that was generated via insertion of an RFP sequence downstream of the TH coding sequence. We validated that endogenous TH expression was unaffected by genetic modification; RFP faithfully mimicked TH expression during differentiation. Use of this TH-RFP reporter cell line enabled purification of mDA-like neurons from heterogeneous cultures with subsequent characterization of neuron transcriptional and epigenetic programs (global binding profiles of H3K27ac, H3K4me1 and 5 hydroxymethylcytosine (5hmC)) at four different stages of development. We anticipate that tools and data described here will contribute to development of mDA neurons for applications in disease modeling and/or drug screening and cell replacement therapies for PD.
2017-01-24 | GSE93905 | GEO
Project description:Background: Parkinson’s disease (PD), a severe threat in aging society, is a significant cause of disable. Curcumin, a polyphenol with hydrophobic properties, has been proved to against Parkinson. Our previous study provides an initial understanding of the neuroprotective mechanisms of curcumin in treating Parkinson’s disease. However, further exploration in this area is needed. The present study was designed to investigate the potential mechanism of curcumin for treating PD. Methods: The therapeutic efficacy of curcumin was evaluated using behavioral tests, immunofluorescence of tyrosine hydroxylase (TH). Network pharmacology and transcriptomics predicted the active pathway and bioprocess of curcumin in PD. Activation of the PI3K / AKT signaling pathway was confirmed by quantitative real-time PCR and immunofluorescence. Result: Curcumin restored the dyskinesia and dopaminergic neurons damage of MPTP-induced mice. The results of network pharmacology and transcriptomics showed that curcumin against Parkinson's disease by regulating inflammation, oxidative stress, and aging. The mechanisms of these were associated with activation of PI3K / AKT pathway. Conclusion: In conclusion, the mechanism of curcumin against PD was revealed by our study which lays a foundation for the application of curcumin in treating.
2023-10-19 | GSE243886 | GEO
Project description:Our goal was to develop a list of genes that could be used effectively to highlight the genomic profiling of human embryonic neural stem cells (hENSCs), and to identify genes involved in the process of their differentiation to dopaminergic (DA) neurons. Our results showed that Agilent's Whole Human Genome Oligonucleotide Microarray permits the monitoring of at least 41000 genes as cells differentiate. In this study, we identified 13525 genes to be differentially expressed between undifferentiated hENSC and DA cells isolated from human substansia nigra. Approximately 3737 genes were up-regulated in the embryonic NSC, and 4116 genes were up-regulated in DA cells. Careful analysis of the emerged data using the web-accessible program named Database for Annotation, Visualization and Integrated Discovery (DAVID) has permitted us to distinguish several genes and pathways that are involved in dopaminergic differentiation, and to identify the crucial signaling pathways that direct the process of differentiation. Our study elucidated that genes related to midbrain development, such as Nr4a2 (nuclear receptor subfamily 4, group A, member 2, Nurr1) and En1 (engrailed 1), were increased to 3.76- and 6.41-folds, respectively. In addition, the transcriptions of the genes for DA neuron phenotype, such as Ddc (doapmine decarboxylase, AADC), Slc6a3 (solute carrier family 6, member 3, DAT), and Th (tyrosine hydroxylase), were significantly increased to 8.08, 4.01, and 5.91, respectively. As data accumulate with different populations and different methods of differentiation, one will perhaps be able to identify the key regulators and biomarkers that may allow selective selection of limited number of genes or transcription factors to be used for direct reprogramming of NSC into DA cells, with an ultimate goal of obtaining different types of allogenic neurons including personalized DA neurons to be used in replacement therapy for neurodegenerative diseases such as Parkinson's disease (PD). Two-condition experiment: hENSC S vs. DA cells. Biological replicates: 2 hENSC, and 2 DA neuron samples from human substantia nigra cells.
2011-10-26 | E-GEOD-25931 | biostudies-arrayexpress
Project description:Therapeutic strategies that enhance anti-viral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The co-inhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections 1-4. In addition, PD-1+ CD4+ T cells constitute a significant fraction of the HIV/SIV viral reservoir5-7. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of anti-viral CD8+ T cells and B cells 4,8. However, the immunological effects of PD-1 blockade during anti-retroviral therapy (ART) and the potential to destabilize the persistent HIV/SIV reservoir have not been studied. Here, we show that administration of anti-PD-1 antibody (PD-1 Ab) 10 days prior to initiation of ART rapidly enhanced anti-viral CD8+ T cell function and diminished interferon stimulated genes (ISGs) that resulted in markedly improved viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. In addition, PD-1 blockade during suppressive ART resulted in transient increases in plasma viremia, induction of gene signatures associated with effector CD8+ T cell function and ISGs, and lower levels of cell associated replication-competent virus suggesting destabilization of the viral reservoir. Following ART interruption, PD-1 Ab treated animals showed markedly higher expansion of proliferating CXCR5+ Perforin+ Granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in delayed viral rebound and better control of viremia. PD-1 blockade administered only during suppressive ART however was only partially effective. Our results indicate an optimal regimen of PD-1 blockade administered in combination with ART, that augments anti-viral CD8+ T cell function and reduces the viral reservoir leading to improved control of viral rebound after ART interruption. These results have important implications for developing novel therapeutic interventions to achieve durable remission of HIV.
2021-02-24 | GSE111435 | GEO
Project description:Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. Genomic DNA was isolated from each of the four lines of iPSCs and labeled with Cy5. Pooled sex mismatched normal human genomic DNA was labeled with Cy3. Both samples are hybridized together on RPCI 21K BAC aCGH array.
2012-01-21 | E-GEOD-35190 | biostudies-arrayexpress
Project description:The identified stromal factors SDF1alpha, sFRP1 and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells. Human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons are potentially useful for treating Parkinson’s disease (PD) through cell replacement therapy. Generation of DA neurons from hESCs has been achieved by co-culture with the stromal cell line PA6, a source of stromal cell-derived inducing activity (SDIA). However, the factor(s) produced by stromal cells that constitute SDIA is unknown. We previously reported that medium conditioned by PA6 cells can generate functional DA neurons in the human embryonal carcinoma stem cell line, NTera2. Here we further examined the effects of PA6-conditioned medium and found that it can induce DA neuronal differentiation in both the NTera2 cell line and the hESC line, I6. To identify the factor(s) responsible for SDIA, we used large-scale microarray analysis of gene expression combined with proteomic analysis of PA6-conditioned medium. Four candidate factors (hepatocyte growth factor (HGF), stromal cell-derived factor-1 alpha (SDF1alpha), secreted frizzled-related protein 1 (sFRP1) and vascular endothelial growth factor D (VEGFD)) were identified and immunoaffinity capillary electrophoresis (ICE) was used to establish the protein concentration of these factors in conditioned medium. Upon addition of SDF1alpha, sFRP1, and VEGFD, we observed an increase in the number of tyrosine hydroxylase- and TuJ1- positive cells in both the NTera2 and I6 cell lines. These results indicate that SDF1alpha, sFRP1 and VEGF-D are major components of SDIA, and suggest the potential use of these defined factors to elicit dopaminergic differentiation of pluripotent stem cells as a therapeutic intervention in PD. Mouse embryonic fibroblasts were grown in DMEM medium supplemented with 10% FBS; this conditioned media was used as the control. PA6, mouse stromal cells, were grown in MEM-alpha supplemented with 10% FBS; this conditioned media is known to induce differentiation in hES cells.
2012-06-24 | E-GEOD-20503 | biostudies-arrayexpress
Project description:Parkinson disease (PD) is characterized by extensive loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). A strong association has been reported between PD and exposure to mitochondrial toxins such as the environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived, stem cell model of PD that allows comparison of -synuclein ( -syn) mutant cells and isogeneic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations specific to A53T -syn mutant A9-DA neurons (hNs). We report a novel molecular pathway whereby basal as well as toxin-induced oxidative and nitrosative stress inhibits the MEF2C-PGC1 transcription network in A53T hNs compared to corrected controls, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small molecule high-throughput screening, we identify the MEF2C-PGC1 pathway as a new drug target for therapeutic benefit in PD. In the current study, isogenic hiPSCs differing exclusively at a single amino acid (A53T) were exposed to either 2.8uM paraquat in combination with 1uM maneb for 24h or PBS vehicle control. Gene expression profile was analysed to assess the effect of both the genotype and exposure regiment on gene expression.
2013-12-05 | E-GEOD-46798 | biostudies-arrayexpress
Project description:Our goal was to develop a list of genes that could be used effectively to highlight the genomic profiling of human embryonic neural stem cells (hENSCs), and to identify genes involved in the process of their differentiation to dopaminergic (DA) neurons. Our results showed that Agilent's Whole Human Genome Oligonucleotide Microarray permits the monitoring of at least 41000 genes as cells differentiate. In this study, we identified 13525 genes to be differentially expressed between undifferentiated hENSC and DA cells isolated from human substansia nigra. Approximately 3737 genes were up-regulated in the embryonic NSC, and 4116 genes were up-regulated in DA cells. Careful analysis of the emerged data using the web-accessible program named Database for Annotation, Visualization and Integrated Discovery (DAVID) has permitted us to distinguish several genes and pathways that are involved in dopaminergic differentiation, and to identify the crucial signaling pathways that direct the process of differentiation. Our study elucidated that genes related to midbrain development, such as Nr4a2 (nuclear receptor subfamily 4, group A, member 2, Nurr1) and En1 (engrailed 1), were increased to 3.76- and 6.41-folds, respectively. In addition, the transcriptions of the genes for DA neuron phenotype, such as Ddc (doapmine decarboxylase, AADC), Slc6a3 (solute carrier family 6, member 3, DAT), and Th (tyrosine hydroxylase), were significantly increased to 8.08, 4.01, and 5.91, respectively. As data accumulate with different populations and different methods of differentiation, one will perhaps be able to identify the key regulators and biomarkers that may allow selective selection of limited number of genes or transcription factors to be used for direct reprogramming of NSC into DA cells, with an ultimate goal of obtaining different types of allogenic neurons including personalized DA neurons to be used in replacement therapy for neurodegenerative diseases such as Parkinson's disease (PD).
2011-10-27 | GSE25931 | GEO